The overarching goal of this RO1 is to elucidate the molecular basis of melanoma metastasis so to inform the rational development of therapeutic agents that can halt disease progression. Our strategy is to discover and characterize new melanoma metastases genes utilizing an integrated approach that encompasses genomic characterization of staged mouse and human melanomas, functional genetic screens of metastases candidates, rigorous validation and mechanistic study in robust biological systems, including genetically engineered mouse (GEM) models and human clinical specimen. In current award, we have generated and characterized a Met-driven metastatic melanoma model and demonstrated the importance of HGF-Met paracrine signaling in metastasis. Genomic characterization of metastatic melanomas from this and other GEM models has led to the identification of a novel melanoma metastasis gene, NEDD9, a member of the CAS family. Mechanistically, we showed that NEDD9 functions to enhance and maintain focal contacts required for cell migration and invasion, and such activity of NEDD9 is dependent on focal adhesion kinase. In addition, a systematic cross-species comparative oncogenomic analysis of primary and metastatic melanomas has identified an additional 121 candidate metastasis genes that are being enlisted into functional validation. Building on our progress, this renewal application will explore the tumor biological roles of NEDD9 in metastasis initiation, progression and maintenance using inducible GEM model, and pursue the validation of new metastasis candidates through low-complexity in vivo genetic screens followed by rigorous functional and clinical validation in human melanoma cells and melanoma specimen on TMA, respectively